Novel beta-(substituted amino)propiophenones



United States Pat n F US. Cl. 260-519 4 Claims ABSTRACT OF THEDISCLOSURE a-(substituted amino) propiophenones are disclosed. Thephenyl group may be substituted by alkyl, hydroxy, alkoxy, amine,alkanoyloxy, alkylamino, alkanoylamino, chloro and bromo radicals. Thecompounds exhibit use as bactericides and as chelating agents.

This application is a division of co-pending application Ser. No.523,925 filed Feb. 1, 1966, the latter application in turn being acontinuation-in-part of, nowabandoned, application Ser. No. 386,041filed July 29, 1964.

This invention relates to a novel'seriesof'Ma'nnich agents. Moreparticularly it relates to a series of Mannich bases derived fromacetophenones and amino acids and to the phannaceutically acceptablesalts, esters and amides thereof which are valuable bactericides andpolyvalent metal ion deactivators. p

The novel compounds of this inventionhave the-general formula R isselected from the group consisting of hydroxy, lower alkoxy, amino,lower alkanoyloxy, lower alkylamino, lower alkanoylamino, chloro andbromo; I

R is selected from the group consisting of hydrogen and lower alkyl; and

R is selected from the group consisting of each of R and R is selectedfrom the group consisting of hydrogen, lower alkyl, hydroxy, loweralkoxy, amino,

3,514,481 Patented May 26, 1970 lower alkanoyloxy, lower alkylamino,lower alkanoylamino, chloro and bromo.

The terms lower alkyl, lower alkanoyl and lower alkoxy as used hereinrefer to alkyl, alkanoyl and alkoxy groups having from one to fourcarbon atoms and includes the branched-chain and straight-chain radicalsof the alkyl, alkanoyl and alkoxy groups having 3 and 4 carbon atoms.

Also included within the ambit of this invention are the lower alkylesters, the unsubstituted amide derivatives, the pharmaceuticallyacceptable acid and base salts'of these amphoteric substances, theracemic (optically inactive mixture) and the stereoisomeric forms (D-and L-) of these novel compounds. Of particular value are the mineralacid addition salts, e.g., hydrochlorides, sulfates, the lower alkanoicacid salts, e.g., acetates, propionates,

. butyrates and salts of such organic acids as citric, gluconic acids;the alkali metal salts such as sodium and potassium salts.

The valuable compounds of this invention are readily prepared by methodswell known in the art. The mostconvenient methods from the standpoint ofavailability of materials, ease and simplicity of reaction, yield andpurity of product are the Mannich reaction and the exchange reactionbetween the appropriate B-dimethylaminopropiophenone and the desiredamino acid.

The well-known Mannich reaction consists in the condnsation of -thedesired amino' acid eiierallas the bases which are effective asbacterlcldesand as chelatlng g y hydrochloride salt, with-formaldehydeand the appropriate acetophenone. The formaldehyde may be used as anaqueous solution, e.g., formalin, or as paraformaldehyde. When aqueousformaldehyde is used the condensation is usually conducted by agitatingthe reactants in the absence of an organic solvent. It may also becarried out by 'the addition of a water soluble organic solvent such asa lower alcohol, e.g., methanol, ethanol. The use of paraformaldehyde asformaldehyde source requires the use of an organic solvent such asethyl, isopropyl and isoamyl alcohol. Alternatively, the acetophenonereactant may be used as solvent if it is a liquid at the reactiontemperature. In such instances, a sufiicient excess of the acetophenonereactant is added to permit good agitation, e.g., shaking or stirring.

-, The reaction .is generally conducted at the reflux te perature of thesolvent for periods ranging from a few minutes to several hours. Thereaction time, of course,

depends upon the nature of the reactants and the boiling point of thesolvent. The acetophenone, formaldehyde and amino acid reactants aregenerally used in 'the molar proportions of 1.00 to 1.5-2.0 to1.05-4.10.

The B-dimethylaminopropiophenone reactant utilized in the exchangereaction isaMannich base type compound and is prepared as describedabove. The exchange reaction, in general,-comprises, reaction of the,B-dimethylaminopropiophenone as the hydrochloride salt with asubstantially equimolar amount of the desired amino acid in aqueoussolution at a temperature of from about C. to the reflux temperature.The reaction time, as expected, is dependent upon the nature-of thereactants and the temperature. It is, however, generally completed inperiods of from 5 minutes to 30 minutes.

All the novel compounds of this invention exhibit activity asbactericides against a wide variety of microorganisms includinggram-positive and gram-negative bacteria. Their surprising broadspectrum and high potency can be demonstrated by in vitro tests againstvarious organisms in a brain-heart infusion medium by the usual two-foldserial dilution technique.

The in vitro antibacterial activity, expressed in mcg./ ml. of severalof the novel and valuable compounds of this invention versus a number ofmicroorganisms is given below. The compounds represented by the numbersare:

( 1 N- fl- (o-hydroxyb enzoyl) ethyl] glycine (2) N- [/8-(o-hydroxybenzoyl) ethyl] sarcosine hydrochloride (3) N- [B-(p-methoxybenzoyl) ethyl] sarcosine hydrochloride (4) D-N- B-(o-hydroxybenzoyl ethyl] threonine (5 L-N- [13- (o-hydroxybenzoyl)ethyl] threonine (6) DL-N- [fi- (o-hydroxybenzoyl) ethyl]threonine (7)DL-N- [13- o-hydroxyb enzoyl) ethyl] threonine hydrochloride 8 L-N- B-(o-hydroxyb enzoyl) ethyl] serine (9) DL-N- [fi- (o-hydroxybenzoyl)ethyl] valine l) D-N- ,8- (o-hydroxybenzoyl) ethyl]valine l 1 L-N- [B-o-hydroxybenzoyl) ethyl valine 12) L-N- [3- (o-hydroxybenzoyl)ethyl]valine hydrochloride 1 3 DL-N- [B- (o-hydroxybenzoyl) ethyl]valine hydrochloride 14) DL- [B- (p-chlorobenzoyl) ethyl]valine 15 DL-N-[fi- (p-methoxybenzoyl ethyl]valine 16) DL-N- )3- (o-hydroxybenzoylethyl] leucine l 7) L-N- [B- o-hydroxyb enzoyl ethyl] leucine l 8) D-N-[fl- (o-hydroxybenzoyl ethyl] leucine 19 D,L-N- [B- (o-hydroxybenzoyl)ethyl] methionine (20) L-N-[p-(o-hydroxybenzoyl)ethyl]methionine (21D-N- [13- (o-hydroxybenzoyl) ethyl] methionine of this invention, manyvariations of which are possible without departing from the spirit orscope thereof.

EXAMPLE I Preparation of D,L-N--[;3- (o-hydroxybenzoyl)ethyl] valine Amixture of 1900.0 g. (8.28 moles offi-dimethylamino-o-l1ydroxypropiophenone hydrochloride, preparedaccording to Taylor and Nobles, J. Am. Pharm. Assn. Sci. Ed. 49, 317(1960), and 9.5 liters of water is heated to 85 C. on the steam bath. Asolution of 969.0 g. (8.28 moles) D,L-valine in 4.8 liters of water isadded all at once and the resulting mixture heated for 10 minutes on thesteam bath. The slurry is cooled to room temperature, filtered, washedwith acetone and dried in the atmosphere to give 1.50 kg. crude product;M.P. 205.0206.0 C. (dec.).

Analysis.Calc. for C H O N (percent): C, 63.39; H, 7.21; N, 5.28. Found(percent): C, 63.50; H, 7.24; N, 4.99.

EXAMPLE II D N- [p- (o-hydroxyb enzoyl) ethyl] valine A mixture of 22.9g. (0.1 mole) of fl-dimethylamino-ohydroxypropiophenone hydrochloride,11.7 g. (0.1 mole) of D-valine and 200 ml. of Water are heated toboiling for 15 minutes. The mixture is allowed to cool, then filteredand the filter cake washed with water and air dried to give M.I.C.(meg/ml.)

Organism 1 2 3 4 6 7 s 9 11 12 13 14 15 16 17 1s 19 20 21 S.t h 6.3 0.393.12 0.78 0.73 1.56 1.56 6.25 3.12 1.56 0.19 1.56 0.78 25 12.5 3.12 6.2512.5 3.12 12.5 3.12 P512 2153- 12.5 0.78 3.12 1.56 1.56 1.56 1.56 6.256.25 1.56 1.56 3.12 1.56 25 100 6.25 6.25 12.5 6.25 12.5 3.12 E. coli6.3 0.19 3.12 1.56 1.56 0.78 0.73 1.56 6.25 0.39 0.19 3.12 0.78 6.2512.5 6.25 6.25 12.5 0.73 6.3 3.12 P5 aeruginosa 100 12.5 25 100 100 1006. 25 50 100 6.25 6.25 50 100 100 100 100 100 100 100 100 6. 25 A.6310051153-- 6.3 0.19 a25 0.78 1.56 1.56 3.12 5.12 1.56 1.56 1.56 0.7312.5 50 6.25 6.25 6.25 3.12 12.5 3.12 S.pyogems 100 50 100 100 100 50 6.25 50 25 12.5 12.5 100 100 100 100 50 100 100 50 100 25MmyogenesvanAureus. 100 100 100 50 50 25 25 100 25 25 25 50 25 100 10050 100 100 50 100 50 P.7nultocida 1.56 50 25 25 12.5 12.5 100 12.5 12.5100 12.5 100 100 50 12.5 12.5 25 25 12.5

In addition to their antibacterial properties these novel 14.5 g. ofproduct; M.P. 205206 C. (dec.). Additional compounds also exhibitantifungal properties. Their general antimicrobial properties renderthem of value for topical application in the treatment of variousinfections, for agricultural use, and for industrial use in suchindustries as the laundry, textile and paper industries in a mannersimilar to that in which the quaternary ammonium compounds now find use.

The novel compounds of this invention also function as chelating agentsfor a variety of polyvalent metal ions especially for the heavy metalions of metals of groups I-B, II-B, VI-B, VIIB and VIII of the PeriodicChart of the Elements, e.g. copper, zinc, cadmium, nickel, cobalt, iron,manganese and chromium. Of particular interest as chelating agents arethose compounds of Formulae I and II wherein R is an ortho hydroxy,lower alkoxy, amino or substituted amino group. The presence of suchgroups enhances chelation by reason of their participation in chelateformation. Additionally, as regards compounds of Formula II, thelocation of the carboxyl group of the aromatic amino acid moiety orthoto the amino (-NH) group and/or the location of R wherein R is hydroxy,lower alkoxy, amino or substituted amino ortho to said amino groupenhances chelate formation. The complexes are somewhat soluble in Waterand quite soluble in nonaqueous solvent systems. This property, ofcourse, renders them useful for a variety of purposes wherein metal ioncontamination presents a problem, e.g., stabilizers in organic systems,metal extraction, biological experimentation. They are further useful inthe analysis of polyvalent metal ions which may be complexed orextracted by these materials and as metal carriers. Other uses common tosequestering agents are also apparent for these cornpounds.

The following examples are solely for the purpose of illustration onlyand are not to be construed as limitations product can be obtained byevaporation of the mother liquor to small volume.

Purification is accomplished by suspending the solid in water (1 g./16.5 ml.), heating to boiling and adding sufficient dilute acetic acidto produce a clear solution. The hot solution is filtered and cooled togive the crystalline product; M.P. sinters at C., melts at 209210 C.(dec.) [a] E62.9 (in acetic acid).

Analysis.-Calc. for C H O N (percent): C, 63.39; H, 7.21; N, 5.28. Found(percent): C, 63.49; H, 7.10; N, 5.17.

EXAMPLE III L-N- 8- (o-hydroxyb enzoyl )ethyl] valine The procedure ofExample II is repeated but substituting L-valine for D-valine to give 13g. of product; M.P. 104206 C., melts at 209-210 C. (dec.)

5] E+63.2" (in acetic acid).

Analysis.Calc. for C H 0 N (percent): C, 63.39; H, 7.21; N, 5.28. Found(percent): C, 63.43; H, 7.02; N, 5.04.

The hydrochloride salt is prepared by passing dry hydrogen chloride gasinto an isopropyl alcohol suspension of the product until a clearsolution results. On evaporation to small volume the salt crystallizes.It is removed by filtration, washed with isopropyl alcohol ether thendried; M.P. ISO-181 C. (dec.).

Analysis-Cale. for C H O NCl (percent): N, 4.65; Cl, 11.75. Found(percent): N, 4.62; Cl, 11.72.

EXAMPLE IV [,8- (o-hydroxybenzoyl)ethyl] glycine Method A.-To 23.0 g.(0.20 mole) of B-dimethylamino-a-hydroxypropiophenone hydrochloride in200 ml.

of water is added 15.0 g. (0.20 mole) of glycine and the mixture heatedat 90-95 C. for 20 minutes. The yellow solution is allowed to cool to 50C., filtered to remove some oily material, then chilled for severalhours. .Scratch- EXAMPLE VI I The following compounds are prepared bythe procedure of Example V from the appropriate reactants.

Compound M.P. C.) (dee.)

DL-N-[fl-(p-Chlorobeuzoyl)ethyl]valine., 218-220DL-N-IB-(p-Chlorobenzoyl)ethyl1valine-HC1 77-80 L-N-[B-(o-Hydroxybenzoyl) ethyl1serine- 209-211 DL-N-[B-(o-Hydroxybenzoyl)ethyl serine. 205-207 DL-N- fl-(o-Hydroxybenzoyl) ethyl serlne-HOL168-170 DL-N- B-(o-Hydroxybenzoyl) ethyl -,a-alanine. I 211-214 L-N-[fi-(o-Hydroxybenzoyl) ethylg-a-alanine 207-209L-N-[B-(o-HydroxybenzoyDethyl -a-alanine-HGL 153-156DL-N-[B-(o-Hydroxybenzoyl) ethyll-a-methylmethiomne 238-241L-N-lB-(o-Hydroxybenzoyl) ethyl]methionine 200-202 D-N-[fl-(o-Hydroxybenzoyl) ethyl]methionine 202-204 DL-N-[B- (Hyd.toxybenzoyl)ethyl methionine 199-201 DEN-[B-(o-Hydroxybenzoyl) ethyl methionine-HG115-120 DL-N-[B-(O-Hydroxybenzoyl) ethyl leueine 210-212L-N-[fl-(o-Hydroxybeuzoyl)ethyl]1eucine 206-210D-N-[B-(o-Hydroxybenzoyl) ethyllleucine. 204-205DL-N-[fl-(o-Hydroxybenzoyl) ethyl]threonine 194-197DL-N-[fl-(o-HydroxybenzoyDethyl]threonine-HC 176-178 D-N-[B-(o-Hydroxybenzoyl) ethyl] threouine- 206-208L-N-[fl-(o-Hydroxybenzoyl)ethyl]threon.ine 211-213DL-N-[B-(o-Hydroxybenzoyl) ethyllethionine 203-205DL-N-[fl-(o-Hydroxybeuzoyl) ethyl]ethionine-HO1 82-84 N-[fl-(o-Hydroxybenzoyl)ethylsareosine 208-210 N-[ fl-(o-Hydroxybenzoyl) ethylsarcosine'HCl 162-170 N-[B-(o-Hydroxybenzoyl) ethyl-3-chloro-4-carboxyaniline 208-209 N-[B-(o-Hydroxybenzoyl) ethyl-3-chloro-4-oarboxyaniline-HC1 5-167 N-[B-(o-Hydroxybenzoyl) ethyl-a-amin0salicylic acid. 5 N-[B-(o-Hydroxybenzoyl) ethyl anthranilic acid177-179 N-[/ -(O-Hydroxybenzoyl) ethyl anthranllie acid-HO 156-163N-IB-(o-Hydroxybenzoyl) ethyl -p-aminobenzoic acid- 218-220 N-[fl-(o-Hyd.roxybenzoyl) ethyl -p-aminobenzoic acid-H01 162 1 Preparedby the Mannich reaction of Example 1V.

ing the walls, of the container promotes crystallization. The solid isremoved by filtration, Washed with water and then air dried (11 g.).Additional product is obtained from the mother liquior by evaporation tosmall volume and addition of ethanol to theconcentrate (15.4 g.).

Two recrystallizations of the product from ethanol produceotf-white=yellow crystals; M.P. sinter at 170 C., melt at 204-206? C.(dec.). I

Analysis-Cale. for C H O N (percent): C, 59.18; H, 5.87; N, 6.27. Found(percent): C, 59.00; H, 5.92; N,

Method B-Mar'znich reaction.--A mixture of 13.6 g. (0.1 mole)o-hydroxyacetophenone, 4.5 g. (0.15 mole, 12.2 ml. of 37% solution) offormaldehyde, 11.2 g. (0.1 mole) glycine hydrochloride, 150 ml. ofisopropyl alcohol and 5. drops of concentrated hydrochloric acid are,refluxed'fo'r'l'hour'. Ail additional 4.5 g. of formaldehyde is addedand the mixture refluxed for 45', minutes more. A final 4.5 g. portionofformaldehyde is-added, the mixture refluxed 1 hour then distilled toconstant temperature and allowed to' cool. After, standing for 2idaysthe. mixture is evaporated to small volume and allowed to'stand. After 5days the white solid was filtered OE and dried to give the hydrochloridesalt of the desired product.

, EXA P E DL-N-[fi-(p-methoxybenzoyl)ethyl] valine.

fi-Dirnethylamino 7 p methoxypropiophenone (24.3 g., 0.1 mole) is addedto'a solution of DL-va'li'ne (11.7' g., 0.1 mole) in 100 ml. water andthe mixture heated to boiling for 15 minutes. The pale yellow reactionmixture, containing some crystalline product is cooled, filtered, thefilter cake washed wtih water and dried in air. The mother liquor isboiled for 10 minutes and the crystalline solid recovered in the samemanner as the first crop. Total yield=15.0 g.; M.P. 213414" c. (dec.).

Analysis.-Ca1c., for C H O N (percent): N, 5.02. Found (percent): N,5.05.

A portion of the product is suspended in isopropyl alcohol and dryhydrogen chloride gas passed in until a clear solution results.Evaporation of the solvent gives an oil which becomes crystalline upontrituration with ether. The hydrochloride salt melts at 140-144 C.(dec.).

EXAMPLE VII The procedure of Example V is utilized to prepare thefollowing compounds:

N- 3- o-butoxybenzoyl) ethyl] glycine N- [f]- m-butoxybenzoyl) ethyl]glycine N- [,8'-'(p-butoxybeiizoyh'ethyl] glycine N- [B-(o-butoxyhenzoyl) ethyl] valine N- [0- o-ethoxyb enzoyl ethyl] valine N-[5- (m-ebromobenzoyl) ethyl] valine N- 3- (p-acctoxybenzoyl) ethyl]valine N- [13- (o-methoxybenzoyl) ethyl] glycine I N- [[3- (o-p ropoxybenzoyl) ethyl] glycine N- [0- o-isopropoxyb enzoyl) ethyl] glycine N-[13- (o-aminobenzoyl) ethyl] glycine N- [,8- o-aminobenzoyl) ethyl]-u-alanine N- [/3- (o-aminobenzoyl) ethyl] serine N- [13-(o-aminobenzoyl )ethyl] threonine N- [fl- (o-aminobenzoyl) ethyl]methionine N- [B- (o-aminob enzoyl) ethyl] valine N- [[3-(m-aminobenzoyl) ethyl] valine N- [,8- (p-aminob enzoyl) ethyl] valineN- [B- (p-acetaminobenzoyl) ethyl] valine N- [0- p-acetaminobenzoyl)ethyl] leucine [fi-(p-butyrylaminobenzoyl) ethyl] leucine N- [B-(p-hydroxybenzoyl)ethyl]valine [5- (P- y y y hyl] -a'-mcthylmethionineN- [/3 (m-hydroxybenzoyl)ethyl]sarcosine N- [0- (m-ethoxybenzoyl) ethyl]sarcosine [13- (p-methylaminobenzoyl) ethyl] valine N [fi-(p-butylaminolbenzoynethyl] valine N [B- (m-methylaminobenzoyl) ethyl]valine N- [,B- o-methoxybenzoyl) ethyl] ethionine N- [13- (o-hydroxybenzoyl ethyl] -Nethyl glycine [fi- (o-hydroxyb enzoyl) ethyl] -N-buty1glycine -lfl-( y y y )ethylJ-N-meth l leucine [43- o-hydroxybenzoyl)ethyl] -N-isopropy1 leu i [B- (P methoxybenzoyl) ethyl] -N-methyl valineN- [0- (o-acetoxyb enzoyl) ethyl] valine N- [,8- o chlorobenzoyl) ethyl]valine N- 3- (p-lbromob enzoyl) ethyl valine (vy ybenzoyl) ethyl]sarcosine N- ,B- m-chlorobenzoyl ethyl] valine N- [,B-(o-isopropoxybenzoyl) ethyl] threonine 7 EXAMPLE VIII Compounds of theformula below are prepared according to the procedure of Example Vstarting with the appropriate reactants.

H G O O H -o-oH=-on2-Nn (1) (a s p-OH H 2 13-011 H a p-OH 2-CHa 4 0-0CH: H 2 o-OCrHa H 2 p-OCHs H 2 m-OCH; H 2 o-CH; 2-011 4 O-CHs H 4 p-CHsH 4 p-i-O H H 4 o-NH, 3-011 4 o-NH: 33-00113 4 O-NHCH: B-OCHa 4 p-NHCOCH; on 4 o-OH 2-011 4 o-OH: 2-C4Hv 4 o-OH 2-0011: 4 o-Cl 0H 4 o-Cl3-011 4 o-Br 3-0H 4 -Bl' 3-011 4 o-OCOCHa H 4 o-OCOGsH1 H 4 E0 C O OH: H4 H 4 H 2-013: 4 p-OCOCHa H 2 p-NH: 2-NH1 4 p-NH: z-Nnom 4 o-OH 4NHCOCH; 3 o-OCOCHz B-OCOOH: 4 o-OCH; Br 4 o-OH 4-NH't-C4Ho 3 o-Cl 2-01 4 H2-NH: 4

EXAMPLE IX The acid salts of the novel amphoteric compounds of thepreceding examples are prepared by the following methods.

The hydrochloride salts are conveniently made according to the proceduredescribed in Example V. Alternatively, anhydrous ether can be used inplace of isopropyl alcohol.

Other acid salts, e.g. sulfate, acetate, propionate, butyrate, citrategluconate are prepared by combining equimolar quantities of the desiredacid and amphoteric compound in water, heating to complete reaction, andrecovering the acid salt by evaporation in vacuo, freeze drying orprecipitation by means of a water immiscible organic solvent.

EXAMPLE X The alkali metal salts are obtained by neutralizing, inaqueous solution, the amphoteric compound with the desired base such assodium hydroxide, potassium hydrox ide or by reaction with otassium2-ethylhexanoate. The salt is recovered by lyophilization or by freezedrying.

EXAMPLE XI The chelating capacity of the novel compounds describedherein is demonstrated as follows: 10- mole of cerous acetate zincchloride chromium acetate calcium acetate manganese chloride cupricchloride nickel chloride cobaltous nitrate ferrous sulfate furicchloride cadmium acetate Each of these preparations is conducted at pHvalues of 2, 5, 7 and 10.

What is claimed is:

1. A compound selected from the group consisting of those having theformula i il-CHz-CHz-NH and the pharmaceutically acceptable saltsthereof wherein each of R and R is selected from the group consisting ofhydrogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, amino,lower alkylamino, lower alkanoylamino, chloro and bromo.

2. The hydrochloride salt of the compound of claim 1 having the formulaCOOH I iF-CHz-CHz-NH I OH O 0 OH 3. The compound of claim 1 having theformula 0 yl-GHz-CHz-NH I OH O O OH I OH 4. The compound of claim 1having the formula References Cited UNITED STATES PATENTS 3,120,551 2/1964 Goldschmidt 260519 LORRAINE A. WEINBERGER, Primary Examiner L. A.THAXTON, Assistant Examiner US. Cl. X.R.

